1

Chemistry II (Organic)

Heteroaromatic Chemistry

LECTURES 2 & 3

Ring synthesis: cyclocondensations and

cycloadditions

Alan C. Spivey a.c.spivey@imperial.ac.uk

Feb 2012

2

Format & scope of lectures 2 & 3

• Ring synthesis:

– cyclisations vs. cycloadditions

• Cyclisation/cyclocondensation reactions

– essential functional group chemistry

• imines & enamines

• carbonyls, enols & enol ethers

• thiocarbonyls, ene thiols & thioenol ethers

– kinetics & thermodynamics of ring closure

– common strategies for cyclisations

• 5-membered rings

• 6-membered rings

– design considerations

• Cycloaddition reactions

– 5-membered rings – 1,3-dipolar cycloadditions [3+2]

– 6-membered rings – hetero-Diels-Alder reactions [4+2]

• Supplementary slides 1-7

– some background information

Two Distinct Strategies for Ring Formation

There are 2 distinct ways in which heterocyclic aromatic compounds can be prepared:

stepwise formation of linear cyclisation precursor

formation of 1 new bond during ring-closure

C-C or C-het bond

triggered by nucleophiles, electrophiles, radicals etc.

concerted formation of 2 new bonds

Pericyclic mechanism

C-C and/or C-het bonds

convergent (efficiency, diversity)

AB

C

E D

CB

A

B

C

AF

ED

B

C

AF

ED

B

C

AF

ED

H

LG

hetero-Diels-Alder reactions give 6-memb rings

1,3-dipolar cycloadditions give 5-memb rings

X

X

X X

or

X

N

X

or

X

LG-H

E D

5-memb rings

6-memb rings

Cyclisation Reactions - Essential Functional Group Chemistry - imines

Imines – formation:

carbonyl + 1° amine → imine:

overall:

need H+ but if too much acid is present → protonates amine → stops nucleophilic addition. pH 4.5 is a

compromise. For the reverse process, low pH → fast,~irreversible reaction (amine protonated → salt)

reversible:

carbonyl form is thermodynamically most stable (C=O ~749 kJmol-1 cf. C=N ~607 kJmol-1)

need to drive off water (i.e. a dehydration/condensation reaction):

– heat (>100 °C for H2O)

– 3 Å MS (Molecular Sieves) – zeolites

– azeotropic distillation – ‘Dean-Stark trap’ (e.g. benzene – H2O)

– chemical dehydration – e.g. POCl3 or c.H2SO4

O NR

NH2R

pH 4.5 optimum

strong acid

H2O+ +

Cyclisation Reactions - Essential Functional Group Chemistry - enamines

Enamines – formation:

carbonyl + 2° amine → enamine:

last step is different:

overall:

of course, imines can also form an enamine tautomer

but usually the imine form is preferred thermodynamically…except in special circumstances

O NRRpH 4.5

NHR2 H2O+ +

strong acid

Cyclisation Reactions - Essential Functional Group Chemistry – imines & enamines

Imines & enamines – intramolecular formation, i.e. ring-closure:

retrosynthetic analysis:

Imines & enamines - reactivity:

imines are ELECTROPHILES; enamines are NUCLEOPHILES:

Intramolecular reactions can lead to ring-closure...

Cyclisation Reactions - Essential Functional Group Chemistry – carbonyls & enols

Carbonyls, enols & enol ethers – intramolecular formation, i.e. ring-closure:

retrosynthetic analysis:

Carbonyls, enols & enol ethers – reactivity:

carbonyls are ELECTROPHILES; enols & enol ethers are NUCLEOPHILES:

Intramolecular reactions can lead to ring-closure...

...revise acid and base catalysed aldol reactions (see supplementary slides 1-2)

Oenol ether OHO

Cyclisation Reactions - Essential Functional Group Chemistry – thiocarbonyls & ene thiols

Thiocarbonyls, ene thiols & thioenol ethers – intramolecular formation, i.e. ring-closure:

retrosynthetic analysis:

Thiocarbonyls, ene thiols & thioenol ethers – reactivity:

thiocarbonyls are ELECTROPHILES; ene thiols & thioenol ethers are NUCLEOPHILES:

Intramolecular reactions can lead to ring-closure...

thiols are MORE nucleophilic than alcohols & thiocarbonyls are MORE electrophilic than carbonyls

Sthioenol ether XHS

X = O or S

Cyclisation Reactions - Essential Functional Group Chemistry – thiocarbonyls & ene thiols

Thiocarbonyls, ene thiols & thioenol ethers – formation:

thiocarbonyls are generally prepared from the corresponding carbonyl compounds:

typically use P2S5 or Lawesson’s reagent (e-EROS):

reactions driven by strength of P=O vs. P=S bond

thiols are generally formed by substitution of a leaving group (LG):

CAUTION... most thiol and thiocarbonyl compounds STENCH!

thiolNaSHLG SHSN2

+

Cyclisation Reactions – Thermodynamics & Kinetics of Ring Closure

Intra-molecular ring-closure vs. inter-molecular oligomerisation/polymerisation:

entropy is the key factor:

concentration of the reaction – high dilution favours ring-closure

ring size formed – smaller rings favoured (but...see below)

Ring-closure under thermodynamic (TD) control (i.e. reversible conditions):

many reactions forming heteroaromatic products are driven by:

favourable DS° due to loss of small molecule (as vapor at high temperature → irreversible)

i.e. cyclodehydrations (-H2O) & cyclocondensations (-H2S, NH3, MeOH etc.)

favourable DH° due to stability of aromatic product

Ring-closure under kinetic control (i.e. irreversible conditions):

less common when forming heteroaromatic products, but does affect the rate of TD controlled reactions:

variable DS# - critically dependent on ring size & hybridisation of reacting centres - Baldwin’s rules

(see supplementary slides 3-4)

DG#

DH#

= - TDS#

free energy of activation:

DG DH= - TDS°free energy of the reaction:

DG

reaction co-ordinate

DG#

DG

Nu

E

ring-closure

oligomerisation/polymerisation

=

Cyclisation Reactions – Common Strategies for 5-Membered Rings

2 common strategies for cyclisations:

for synthetic equivalents of these ‘synthons’ and others (see supplementary slide 5)

the exact sequence of individual steps for most cyclocondensation reactions is unknown and will vary with

reaction conditions (solvent, temperature, pH etc.) – seek plausible pathways

X

X

X

TYPE I: 2 x C-X bond formation

TYPE II: 1 x C-X bond & 1 x C-C bond formation

Xor

Cyclisation Reactions – Common Strategies for 6-Membered Rings

2 common strategies for cyclisations:

for synthetic equivalents of these ‘synthons’ and others (see supplementary slide 5)

X

TYPE I: 2 x C-X bond formation

TYPE II: 1 x C-X bond & 1 x C-C bond formation

N

X

or

X

Cyclisation Reactions – Design Considerations

Considerations during retrosynthetic analysis – synthesis design:

identify strategic bond disconnections – seek maximum convergence

identify synthons with simple, readily available synthetic equivalents (see supplementary slide 5)

avoid substrates with multiple possible enol/enolate forms:

pay attention to oxidation level – is the degree of unsaturation correct to avoid need for oxidation?

what functional groups are required?...introduce before, or after ring formation?

Look out for different tautometic forms of intermediates & products (see supplementary slides 6-7)

H

e.g.

O OHcf.

O H OH OH OH'good' 'bad'

N R'R

H H

H

R R'OO

H

+ NH3

2x H2O

NO

OO

H

oxidation (-2H)

HNO3

HNO2 H2O

NR R'N R'R

H H

H

Cycloaddition Reactions – General Features

Cycloaddition reactions are characterised by:

concerted formation of 2 new bonds (C-C and/or C-het) – no reaction intermediates

asynchronous bond formation – i.e. some build up of charge in transition state as the formation of some bonds

is more advanced than that of others

‘aromatic’ transition state [(4n + 2) p electrons involved] – pericyclic reactions

convergent (efficiency, diversity) but need to control regiochemistry (see later)

5-Membered rings are formed from 1,3-dipolar cycloadditions {[p4s+p2s] pericyclic processes}

reaction of 1,3-dipole with dipolarophile

initial products can be aromatic or require subsequent elimination/oxidation → aromatisation

6-Membered rings are formed from hetero-Diels-Alder reactions {[p4s+p2s] pericyclic processes}

reaction of diene with dienophile

initial products are di- or tetrahydro intermediates – subsequent elimination/oxidation → aromatisation

AB

C

E D

CB

A

E D

Cycloaddition Reactions – 1,3-Dipolar Cycloadditions → 5-Membered Rings

1,3-Dipolar cycloadditions are 6 electron [p4s + p2s] concerted pericyclic reactions:

sometimes referred to as [3+2]-cycloadditions – this refers to the number of ATOMS (not electrons)

There are 2 main classes of dipoles used in 1,3-dipolar cycloadditions:

Most multiple bonds can act as dipolarophiles:

BUT usuallya C=C bond...

AB

C

E D

CB

A

E D

NR NR

NR O

NITRILE IMINES

NITRILE OXIDES

N N CR2

NR S

AZIDES

DIAZO COMPOUNDS

NITRILE SULFIDES

N N NR

LINEAR 1,3-DIPOLES

R A B C

R'

R"

ISOXAZOLES

PYRAZOLES

ISOTHIAZOLES

PYRAZOLES

TRIAZOLES

ISOXAZOLES

TRIGONAL 1,3-DIPOLES

RA

BC

R'"

R"

R'

N

R O

R' R"

NITRONES

C C C C C O C N C N

notes

• 3 atom/4p electron species

• central atom ≠ C

• always have formal charges

• charges @ 1,2- NOT 1,3-positions

• linear are: sp-sp-sp2

• trigonal are sp2-sp2-sp2

• no correlation between reactivity &

geometry

• retrosynthetic ‘signature’ is ≥2

adjacent heteroatoms in the ring

Cycloaddition Reactions – 1,3-Dipolar Cycloadditions – reactivity & regioselectivity

Reactivity is controlled by relative energies of Frontier Molecular Orbitals (FMOs)

the key interaction is between the Highest Occupied Molecular Orbital (HOMO) of one reactant and the Lowest

Unoccupied (i.e. empty) Molecular Orbital (LUMO) of the other reactant

the closer the two interacting orbitals are in energy the faster the reaction rate

consequently, 2 important types can be identified:

Regiochemistry is controlled by:

the polarity of the frontier molecular orbitals (as for hetero-Diels-Alder regioselectivity, see later)

BUT, sterics can override e.g.:

NO

nitrile oxide

(1,3-dipole)

+Bu3Sn

H

alkyne

(dipolarophile)

D80 CO

NO

N+

Bu3SnSnBu3

3,5- & 3,4-di-substitutedisoxazoles

(86 : 14)

Cycloaddition Reactions – hetero-Diels-Alder Reactions → 6-Membered Rings

hetero-Diels-Alder cycloadditions are 6 electron [p4s + p2s] concerted pericyclic reactions:

sometimes referred to as [4+2]-cycloadditions – this refers to the number of ATOMS (not electrons)

Azines are generally prepared by aza-Diels-Alder reactions between aza-1,3-dienes and alkenes/alkynes

usually inverse electron demand

generally give non-aromatic heterocycle → extrusion of small molecule(s) → aromatic species

Most multiple bonds can act as dienophiles:

C C C C C O C N C N

NN

Y

X

N

N

N

N

N

NR2

+

++

+

2-aza-1,3-dienes 1-aza-1,3-dienes

-HNR2

N

N

N+

-4H

-H2X

-N2/HY

Y

-N2/HY2

2

2

1

1

Reactivity is controlled by the relative energies of the Frontier Molecular Orbitals (FMOs)

again, 2 important types:

hetero-diene + all carbon dienophile usually inverse electron demand

all carbon diene + hetero-dienophile usually normal electron demand

hetero-diene + hetero-dienophile rare (tend to have alternative reaction paths available)

Regiochemistry is controlled by the polarity of the frontier molecular orbitals

electron donating and withdrawing substituents perturb energies and sizes of orbitals – most favourable

reactions involve overlap of orbitals of similar size with complementary polarities:

NN

R'

NR2

+

R'

NR2

N

R'+

N

R'R2N R2N

matched polaritymismatched polarity

Cycloaddition Reactions – hetero-Diels-Alder Reactions – reactivity & regioselectivity

Supplementary slide 1 - Essential Functional Group Chemistry – acid catalysed aldol reaction

The acid catalysed aldol reaction:

Overall:

O O OH OH2O

H3O H3OO+ +

aldolcat. cat.

OHO

HOH O

H

OH

OH O OH

OH

OH

H

HO HOOH OH2OO

aldol; can stop here but under

more forcing conditions.....

OH2

nucleophilic enol reacts with highly electrophilic protonated carbonyl group

protonation converts OH into a good LG....

...which can be pushed out by the enol

OH2

protonation of carbonyl leads to formation of enol

OH2

...get acid catalysed enolisation

H2O+

H OH2

H OH2

H2O

H OH2

H OH2

H

H2O

H

Supplementary slide 2 - Essential Functional Group Chemistry – base catalysed aldol reaction

The base catalysed aldol reaction:

Overall:

O O OH OH2O

OHO+ +

aldolcat. cat.

OH

O

H

OO

O

O OHH

O OH

H

O OHO

base catalysed formation of enolate

protonation of alkoxide yields neutral aldol and regenerates base

H2O

over extended time, further base catalsed enolisation and elimination can occur to

give an unsaturated carbonyl compound.

OH

nucleophilic attack of enolate on electrophilic

carbonyl compound

aldol

OH

+ H2OOH+

Supplementary slide 3 – Baldwin’s ‘Rules for Ring Closure’

For kinetically controlled ring closures:

Baldwin J. Chem. Soc., Chem. Commun. 1976, 734 (DOI) & ibid 736 (DOI) & ibid 738 (DOI)

the relative facility of ring-closure depends critically on the ring size, the hybridisation of the reacting centres &

the mode of ring-closure (exo or endo)

tetrahedral systems:

2 to 7-exo-tet are all favoured processes

5 to 6-endo-tet are disfavoured

trigonal systems:

3 to 7-exo-trig are all favoured processes

3 to 5-endo-trig are disfavoured; 6 to 7-endo-trig are favoured

digonal systems:

3 to 4-exo-dig are disfavoured processes; 5 to 7-exo-dig are favoured

3 to 7-endo-dig are favoured

Baldwin’s rules were formulated following analysis of transition state geometries:

Baldwin J. Chem. Soc., Chem. Commun. 1976, 734 [DOI] & ibid 736 [DOI] & ibid 738 [DOI]

Tet - electrophilic centre has sp3 hybridisation - SN2 reaction

evidence for this trajectory see: Eschenmoser Helv. Chim. Acta 1970, 53, 2059 [DOI]

Trig - electrophilic centre has sp2 hybridisation - Nucleophilic addition to carbonyl/imine

evidence for this trajectory see: Burgi J. Am. Chem. Soc. 1973, 95, 5065 [DOI] & Proctor & Dunnitz Helv.

Chim. Acta 1981, 64, 471 [DOI]

Dig - electrophilic centre has sp hybridisation - Nucleophilic addition to nitrile/alkyne

evidence for this trajectory see: Procter Helv. Chim. Acta 1978, 61, 2538 [DOI] & 1981, 64, 471 [DOI]

X = 120°

N:

X

N

X

CN

-

-

#

YX

= 180°

X XY Y

#

+

X = 109°

O

-

OO

XX

-

#

Supplementary slide 4 – Baldwin’s ‘Rules for Ring Closure’ cont.

Supplementary slide 5 – ‘Synthons’* ↔ Synthetic Equivalents

dinucleophiles:

nucleophile/electrophiles:

dielectrophiles:

* The term ‘synthon’ is used rather loosely here to denote the indicated ‘polarity assigned retrosynthetic skeleta’. For clarity and generality,

these lack full indication of oxidation level unlike a true ‘synthon’ (see: Corey & Cheng ‘The Logic of Chemical Synthesis’ Wiley 1989).

X

XH

NH2

NH2

H2NNH2

H2N NH

X

NH3 H2O H2S RNH2

RNHNH2 RNHOH

NH2

X

XX

X X

XX

NH2

RX

NH2

NH2

X

NH2

X

X = S, O, NR

X = S, O, NR

X

X

R

XZ

R'

XR

N

R

R'

H2NX

R

OR'

XHX

XH

R XH

X

R

X

X X = S, O, NR

Cl

X

Z Z = CO2R, CN, SO2RX

ZX

R

X

R

X

R'

X

R

X

R

X

Cl

X

R

X

ClOR

X

Cl

RR'

X

X

R R1

XX

R R'

X

R R OR1

X

RR'

X

XR

OR1

X

X

Cl

NX = S, O, NR

R

X

Cl

Supplementary slide 6 – Tautomerism

Tautomerism in heterocyclic systems:

many heteroaromatic compounds can exist in two or more TAUTOMERIC forms. TAUTOMERS are structurally

distinct isomers in rapid equilibrium (usually). In most cases a proton shifts from one atom to another

do not confuse TAUTOMERS with resonance forms

e.g. 2-hydroxy pyridine and 2- pyridone are TAUTOMERS and are distinct isomers which can be detected

spectroscopically. Each can be represented by a series of resonance structures. The position of the

tautomeric equilibrium can be different in different SOLVENTS

2-hydroxy pyridine is the predominant tautomer in the gas phase

2-pyridone is the predominant tautomer (>9:1 in EtOH) in solution… probably due to hydrogen-bonding:

N N N NOH OH OH OH

2-hydroxy pyridine

NH

NH

NH N

HNH

O O O2-pyridone

O O

tautomeric equilibrium

N

O N

O

H

H

Supplementary slide 7 – Tautomerism & Binding/Reactivity

Heterocyclic tautomerism in biological systems:

tautomer specific H-bonding is important in DNA/RNA base-pairing:

Tautomeric equilibria & the Curtin-Hammett principle:

Curtin-Hammett principle: ‘the ratio of products formed in a kinetically controlled reaction from one starting

material, present in two (or more) rapidly equilibrating tautomeric forms, depends on the relative energies of the

respective transition states NOT the relative ground state energies of the equilibrating tautomers.’

e.g. methylation of 2-pyridone/2-hydroxypyridine:

NH

O N OHN OMe

B

MeI

~9 : 1 (EtOH)

NH

O

N OHN OMe

N O

Me

E

TS#N

TS#O

TS#T